DM is a major global emerging
public health threat and is a marker for increased risk of HBV transmission [14
]. HB vaccine, one of the safest vaccines available in the world [15
], despite being highly efficacious, long term maintenance of its immune-protection evidenced by adequate immunological memory is one of the recent healthcare challenges among this immune compromised vulnerable group [5
Vaccination of diabetic adults [17
] and children [5
] was repeatedly reported to result in low anti-HBs titres compared to normal subjects. A clear association between DM and impaired response was proved among hemodialysis
(HD) patients [18
] and non-renal failure DM subjects [19
]. Similarly, in the present study, diabetic students revealed hypo-responsiveness to HB vaccine 10-17 years after initial vaccination during infancy as compared to non-diabetics, a finding that confirms the decline of anti-HBs titre overtime and matches well the data of most published follow-up studies regarding HB vaccine long-term immune response [5
]. Studying children from HBV high endemic
countries revealed that from four to ten years after vaccination, about 50% of participants had anti-HBs levels less than 10 mIU/ml. Studies conducted in Taiwan showed that the post-vaccination seropositivity rate dropped from 99% at 1 year to 83% at 5 years [20
] and from 71.1% at 7 years to 37.4% at 12 years [21
]. In Alaskan
study, 88% of children who were vaccinated at birth lost their anti-HBs at the age of 5 years [22
]. Likewise, 80-95% lost their protective anti-HBs when tested 13-15 years after vaccination [23
]. The stepwise logistic regression analysis results in the present study also indicated that the age was the only significant factor associated with poor response, one year increase in age was associated with about 30% higher risk of being non-responder (Figure 1).
of anti-HBs at a concentration of ≥ 10 m IU /ml is not necessary for protection, because it is the immune memory that matters as it can outlast the presence of vaccine-induced antibodies, conferring effective protection against acute disease and the carrier state. The presence of HBV- specific immune memory can be demonstrated by administering an additional (booster) dose of the vaccine and measuring anti-HBs responses [24
]. Dentinger et al. [24
] approved that 13-22 years after primary vaccination, one booster was sufficient to elevate anti-HBs titre to the protective level in 93-100% of the vaccines. In addition, 89-100% of booster recipients 4-13 years old children responded to a booster dose of HB vaccine in another study [25
The boosting phase in the present quasi-experimental comparative study further confirms hyporesponsiveness of diabetic students to booster vaccination as compared to non-diabetic healthy controls. Although one booster dose resulted in seroconversion in 100% of our studied seronegative healthy adolescents
, yet it was not sufficient to protect all the diabetics with 15.6% (7/45) of them left non-protected with significant lower mean of anti-HBs titre (124.3 ± 60.4 mIU/ml) than that of the non-diabetic students (149.3 ± 32.0 mIU/ml) (P=0.016). A finding that is comparable to another study conducted by El-desoky et al. [9
] who revealed that after one booster dose, 94.4% of diabetic vs. 100% of non-diabetic children turned seroprotected. Another study revealed that 78.9% of diabetic and 96.6% of non-diabetic hemodialysis patients produced protective anti-HBs levels after the administration of booster doses. The rate of the protective anti-HBs levels in non-diabetics was 1.2 times higher than that in diabetics [26
Moreover, our data indicated that to reach an adequate protection (anti-HBs>100 mIU/ml) against HBV infection among all diabetic and healthy unprotected students, two booster doses were needed by 11.1% of diabetics in comparison to 8.9% of non-diabetic students. Four (8.9%) diabetic students needed a third booster dose to reach full protection in comparison to none of the normal students. Likewise, Ocak and Eskiocak [26
] gave evidence that more than one booster dose was needed to reach protection in diabetic hemodialysis
adult patients. Although up to three booster doses led to a significant improvement in protective response rates, it left 21.1% of diabetic vs. 3.4% of non-diabetics unprotected.
In addition to age, male gender is one of host factors that contributed to decreased immunogenicity
]. In the present study, it is worth to mention that six of the seven non-responders were males. Abdolsamadi et al. [28
] also observed a better vaccine response in women.
The exact mechanism
of lower immunity rates after vaccinating obese subjects is not clear. Arslanoglu et al. [17
] and Ocak and Eskiocak [26
] failed to link obesity with non-response to HBV vaccine among diabetic children and diabetic hemodialysis patients respectively. In contrast, in the present study non-protected diabetics had significantly higher mean BMI as compared to the protected ones. Therefore, studying immune response of obese children to booster doses of vaccine is an urgent issue of public health importance in an HBV endemic area.
In accordance with published data, [29
] frequent hospitalization among diabetics was the only revealed significant factor associated with decreased immune response to vaccine boosting in the present study. The authors attributed this to a worse diabetic status with subsequent lower immunity and the fact that frequent hospitalization exposes diabetic patients to sharing insulin vials and spring-triggered devices as well as frequent injections and needle pricks made them more prone to nosocomial
infections with subsequent impairment of the immunity.
Published results indicated that a high proportion of vaccinated infants and children retain protective concentrations of anti-HBs in adolescence and exhibit a booster response if revaccinated which might be because of natural boosting from exposure
to HBV-infected persons in the household and community [23
]. Marseglia et al. [29
] mentioned that the fact that three diabetics and five controls with anti-HBs median value of 150 mIU/ml reached a level of >1000 mIU/ml 4 years later is consistent with the hypothesis
of anamnestic response after a natural exposure. The above justification matched well our results as it was found that all diabetics (n=4) who were exposed to HBV infection (anti-HBc positive) gained a protective level of anti- HBs after a single booster. Moreover, all the low responders (4 healthy and 4 diabetics) after either 1st
booster doses were anti- HBc negative.
The question that remains to be answered is how long immune memory will last and hence when to provide a booster dose. Bialek et al. [23
] recommended the application of the extra booster dose at age of 4-5 years, while others considered it is unnecessary until 10 years of age [21
]. Moreover, John and Cooksley [31
] did not recommend booster vaccination before 15 years of age. Optimally
, booster vaccination should be recommended at a point in time when majority of vaccinees actually begin to lose protection [32
]. The results of present study verified that incorporating a booster dose of HBV vaccine into the routine childhood vaccination schedule would be best timed at 12 years old for diabetic students while it remains a debatable issue at 13.5 years old for healthy students.
In conclusion, type 1 diabetic adolescents are hyporesponsive to HBV vaccination and show more rapid decline of protective anti-HBs compared to healthy ones. Adequate protection against HBV infection among students with unprotective anti-HBs level could be achieved after two booster doses for healthy students and three booster doses for diabetic ones. Therefore, we recommend a booster dose for diabetic children 12 years after initial vaccination in Egypt.